Neurology Department, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
PLoS One. 2010 Nov 10;5(11):e13861. doi: 10.1371/journal.pone.0013861.
Dyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) therapy for Parkinson's disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition.
METHODOLOGY/PRINCIPAL FINDINGS: Quantitative real-time polymerase chain reaction (PCR) was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson's disease. With this technique, we determined that thyrotropin releasing hormone (TRH) was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes.
CONCLUSIONS/SIGNIFICANCE: TRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson's disease.
与不自主运动和肌肉疼痛性收缩相关的运动障碍是帕金森病标准左旋多巴（L-DOPA，L-3,4-二羟基苯丙氨酸）治疗的常见且严重的并发症。病理性神经可塑性导致感觉运动纹状体中多巴胺受体信号的超敏反应，被认为是这种目前无法治疗的疾病的基础。
方法/主要发现：采用定量实时聚合酶链反应（PCR）评估帕金森病中与 L-DOPA 诱导的运动障碍相关的分子变化。通过该技术，我们确定在对 L-DOPA 治疗产生异常运动反应的半帕金森大鼠多巴胺耗竭纹状体中，促甲状腺素释放激素（TRH）大大增加，相对于对侧非多巴胺耗竭纹状体和非运动障碍对照大鼠纹状体中测量的水平。ProTRH 免疫染色表明，在未发生运动障碍的对照大鼠的多巴胺耗竭纹状体中，TRH 肽水平几乎不存在，但在运动障碍大鼠中，ProTRH 免疫染色在纹状体中显著上调，特别是在感觉运动纹状体中。这种 TRH 肽的上调影响了直接和间接通路的纹状体中型多棘神经元，以及纹状体中的神经元。
结论/意义：TRH 不是已知的关键纹状体神经调节剂，但在实验动物中纹内注射 TRH 可引起异常运动，显然是通过增加多巴胺释放。我们在运动障碍大鼠模型的感觉运动纹状体中发现 TRH 表达的显著和选择性上调表明，TRH 介导的调节机制可能是帕金森病中驱动多巴胺超敏反应的病理性神经可塑性的基础。
